Features - Automation

Thomas Doherty, chief technology officer at ARxIUM (formerly Intelligent Hospital Systems) based in Winnipeg, Manitoba, Canada, has nearly three decades of experience developing medical devices; aerospace applications for aircraft, spacecraft, and satellites; and naval command and control systems in a variety of platforms. He is also co-inventor of 12 patents for technologies deployed in RIVA, a fully automated intravenous (IV) compounding system for pharmacies that has completed nearly 4 million error-free doses across the world. The following are Doherty’s thoughts on automated compounding.

TMD: What is pharmacy compounding?

Doherty: Pharmacy compounding is the combining, mixing, or altering of a drug and other compounds to create specialized medications, often tailored to individual patients. Compounding can be either by hand (manual) or by highly specialized machines (automated).

TMD: Is there a significant risk to manual compounding?

Doherty: No one intends to make errors. The aseptic technique has become very refined, and for the most part, pharmacy technicians do a very good job. But humans are not perfect, and a very small oversight can have huge consequences. For example, in 2007, actor Dennis Quaid’s twin infants received adult doses of a blood thinner – 1,000 times stronger than a pediatric dose – because a pharmacy technician drew medication from a vial with a label that was almost identical to the vial that should have been used. Fortunately, both children survived. But last December, a woman in Oregon died after receiving an IV containing the wrong medication during an emergency room visit – even though the label on the bag listed the medication that was ordered by her doctor. This is why our goal has always been to design technology that could prevent exactly those types of errors.

TMD: How is automated compounding different, and what are the benefits vs. manual compounding?

Doherty: At its most basic level, automated compounding is simply the application of proven robotic technologies in the preparation of IV medications (syringes and IV bags). Available IV compounding technology not only duplicates the manual process, but does so with substantially more accuracy, efficiency, and repeatability.

Automated IV compounding systems remove the primary source of error – humans – from the compounding process. In fact, RIVA has completed nearly 4 million error-free doses. When you look at it from a liability perspective, hospitals really should explore available options to improve safety, especially if available at a reasonable cost. IV automation is commercially available, has proven benefits, and can be implemented cost-effectively.

Automated compounding provides many advantages. Some systems – such as RIVA – already have features that would allow compliance with the Drug Quality and Security Act (DQSA). For example, RIVA provides an electronic audit trail documenting the details of every dose dispensed (including every vial used), an aseptic compounding chamber with ISO Class 5 air, and much more. The process is fully compliant with USP<797> compounding standards, also required by DQSA.

TMD: What kind of research was conducted prior to developing the RIVA compounding system?

Doherty: Automating the medication compounding process is far more complex than many people realize. A number of variables have to be taken into account, including admixture fluid weight, surface tension, specific gravity and viscosity, differences in the diameter of ‘standard’ syringes, the amount of force necessary for needles to puncture a vial stopper, and the list goes on.

To start, we did an analysis of manual compounding. For example, the preparation of a single dose of Vancomycin can involve as many as 42 process steps – from writing and inputting the order, selecting the vial, measuring and mixing the compound, and delivering and administering it to the patient. At that rate, preparing only 24 doses would require more than 1,000 process steps, and they all need to be performed correctly, every time. But, when you examine all the steps involved, there are a number in the compounding process alone where errors can lead to injury. Errors in preparation of IV medications can have significant consequences as they bypass all the body’s defense mechanisms and go right into the bloodstream. By the time you realize there’s a problem, it could be too late.

So, we looked at the processes for making compounded doses in syringes and IV bags in a pharmacy and asked, “What can go wrong?”

The fact is there are many things that can go wrong. Therefore, the goal of an ideal IV compounding automation system is to provide a solution to areas where a fault analysis shows a risk of failure can be mitigated or eliminated. We made a fault tree of all these things – wrong vial, wrong fluid, contaminated surface, and so on. That led us to begin developing a design that would not only mitigate all those failure points, but also have the system verify each step.

Some initial research for development of the RIVA system was done by engineers at the St. Boniface Research Centre in Winnipeg, who helped develop an early tabletop prototype of the system. This research informed the development and design of today’s RIVA system.

TMD: How is automatic compounding designed to be safer?

Doherty: Our goal with the RIVA system was repeatability in IV production, which results in increased accuracy and reduced opportunity for contamination. Repeatability of process is an important concept, as you really want an IV dose to be made under the right conditions, and for those conditions to be the same for each dose made.

As we conceptualized RIVA, we recognized that it needed an engineered environment to protect fluids and interfaces. RIVA is designed so materials don’t go directly into the compounding chamber, which prevents outside air from getting in. Implementing this design feature was a challenge. It required segmentation of the inventory, separate airflow control, and isolation of the compounding chamber. These kinds of details are important because without attention to such areas, the production process for an IV has variability, and if there is variability, there is not repeatability.

Additionally, we have to make sure ISO Class 5 laminar air moves across critical areas at the right velocity. You need to have fans of a certain size and design to move air that quickly. To do this, we patented ceiling designs and membranes that prevent airflow from being turbulent right at the ceiling where it originates. We also needed to pull air away at the bottom or it would be turbulent there – we had to balance the pushing and pulling of air, while keeping the velocity adequate to sweep all the air away. If it is too gentle, dust or particulates can hang in the middle of the chamber – so we designed it to change the air quickly. In fact, if the chamber is breached, it will automatically stop compounding, reject the dose, and then refill the chamber with clean air in less than a minute.

There were other items we considered in the design that may not seem as important, but are key to a successful automated process. For example, RIVA doesn’t store inventory under the area where fluid transfers occur because there is always a chance for a drip. If you look at other automated compounding systems, you’ll see some store inventory in these areas. A drop might fall and no one would ever know.

Another example is surface sanitization. One of the failure points in the process is that if critical surfaces, such as a vial stopper, aren’t sanitized properly, they could contain bacteria. When that surface is punctured with a needle, the bacteria will get into the fluid, so we use UV lighting to kill bacteria on the vial stopper and laminar airflow to ensure any particulate doesn’t land on other critical surfaces.

TMD: Can you explain how each RIVA is manufactured?

Doherty: When manufacturing a system like RIVA, the design the design behind it needs to have some tolerances so that we can fine-tune the alignment and physical interfaces during assembly.

One of the main components of RIVA is the robotic arm, which is purchased pre-assembled and then we teach it the specifics of interacting with its environment. This teaching of the physical interfaces adjusts for any of the tolerances of the assembly when subsystems are built and installed. When you think about it, the robot is a flexible transportation system – it moves a syringe from the inventory to a station, removes the cap, and then weights it at another station. While at that station, a camera looks at it so we can align the slope and bevel of the needle the same way. Then the robot takes it off and hands it to a fixed station where it is gripped at the barrel, plunger, and needle to make sure all those things are straight and aligned. So, the robot moves things around – precisely and quickly, but all the automation is done by fixed units around the cell.

TMD: What is the process for installing RIVA at a pharmacy?

Doherty: Each RIVA is fully assembled at the factory, and then taken apart and transported to the customer. Once on location, the robot is again re-taught as there are slight variances when reassembled. The process is relatively straightforward as in many cases the positions of items are fixed relative to a reference point. Once the robot learns the unique physical position of an interface area, the rest of the interactions become defined.

TMD: Does RIVA need to be installed in a cleanroom?

Doherty: When someone compounds a medication manually, that person works under a laminar hood in a cleanroom to minimize the risk of contamination. RIVA is a self-contained system that does not necessarily need to be installed in a cleanroom – if the room it is placed in meets certain basic attributes.

TMD: Do you think more pharmacies will be using automation in the future?

Doherty: Absolutely. It’s going to come to the point that a pharmacy is going to have to justify not using automation. The awareness of the risks that the facility is accepting by not using automation are only going to increase as more pharmacies implement the technology.

Features - Ergonomics

Laboratory technology provider Thermo Fisher Scientific has developed an ergonomically designed production line for the manual assembly of a new model series of incubators.

Health-conscious workstation design is a top priority, in addition to process and product quality.

Heracell Vios incubators for medical engineering and health research in cultivating human and animal cells are assembled in Langenselbold, Germany, where Thermo Fisher Scientific has consolidated laboratory equipment production.

A successor to Thermo Fisher Scientific’s Heracell model that sold 75,000 units in 15 years, the new series optimizes control behavior, improves protection against contamination, and facilitates operation.

From prototype to production line

To prepare for production of the Heracell Vios, Felix Pergande, technical head of production for Thermo Fisher Scientific, and Stefan Kämmerer, production resources engineer, developed a prototype of the assembly workstation in 2013. They used this workstation to develop a new series production line and a start-up plant in September 2014.

Pergande explains, “During this period of about half a year, we have had the overall responsibility for the incubator production, from organization and material procurement through to quality assurance. We industrialized production in this time. As soon as it is was well engineered, we handed it over to the incubator department.”

For the assembly workstation development, Thermo Fisher Scientific cooperated with Roemheld. Experts in assembly and handling technology, Roemheld is represented in North America by Carr Lane Roemheld of Fenton, Missouri. Roemheld, headquartered in Hessian Laubach, Germany, has been a supplier and partner for the medical engineering manufacturer since 2009.

Carr Lane Roemheld’s assembly and handling modular units consist of numerous modules that provide ergonomic object positioning for manual assembly. Horizontal and vertical rotation, tilting, lifting, placement, and movement are the basic manipulations. The units can be combined into modular systems for loads from 22 lb to 1,325 lb with manual or electrical operation.

A rotary module with media feed-ducts allows for the hydraulic, electrical, or pneumatic operation of devices held by zero-point clamping systems without complex boring.

Focus on ergonomics

Pergande says, “Roemheld’s consultation quality is extremely high. They dedicatedly respond to our individual requirements. In addition, their products are very reliable and can be configured according to our requirements – we do not have to buy anything ready-made.”

For the new manual assembly workstation, ergonomics were of particular significance to Kämmerer. The earlier incubator series had been assembled on height-adjustable tables, but the 40 lb units had to be moved manually without auxiliary equipment.

“For this reason, preassembly of the inner containers required a lot of handling and was physically more demanding,” Kämmerer says. This had to be improved for the production of the new series.

The inside 28" x 18" casing is open to the front for the 42 gallon incubator and is manufactured in Thermo Fisher’s sheet workshop. In preassembly, an employee covers all five sides with heater foils, forcing him to rotate the container several times. Apart from this, a sensor and a fixture have to be mounted. The entire process takes about 45 minutes, then insulation is attached, and the outside casing is assembled over it. The site in Langenselbold has about 150 assembly employees, eight of whom are assigned to manufacture incubators, in one or two shifts.

Four manual workstations

With the support of Manfred Parr, Roemheld’s assembly technology product manager, Kämmerer and Pergande designed a line of four similar assembly workstations, arranged successively. Two of them are suitable for assembling the larger incubator models.

All workstations consist of an electronic shopfloor lift module with a stroke of 8", which can be lifted and lowered by a pushbutton. A rotary module may be released manually in steps of 45°, allowing the fitter to use two foot switches without walking around the container.

“The prototype of the assembly workstations had only one foot switch. In order to be able to work more efficiently, the fitters had the idea of a second foot switch; this suggestion could rapidly be implemented by Roemheld,” Kämmerer says.

After the design of the assembly workstations was completed, he ordered the components from Roemheld and assembled them. To preserve the surfaces during work, he developed a clamping device with brushes on the bearing surfaces to preserve surface finishes.

“The clear position fixation and the defined handling by means of the 45° indices noticeably reduced the risk of dents in the container,” Pergande says. Time savings and cost reduction are not high priorities in this design, though both are achieved.

He emphasizes that ergonomic workstation design contributes to protecting employee health since “the absence of an employee costs money, because either we cannot produce or we have to assign a replacement.”

“An ergonomic workstation with useful features like this is invaluable. It is good for the back, neck, and shoulders and is a noticeable relief. The body feels it immediately,” says equipment fitter Steffen Hillescheim.

Thermo Fisher Scientific intends to improve other single workstations and entire lines under lean manufacturing aspects in the future.

“This will also include the analysis of handling aspects,” says Pergande. “Since it is often inefficient to reduce wage cost by automation, we want to design our manual workstations as ergonomically and efficiently as possible.”

The standard interface conception of the modular units is helpful in this regard, because it allows for the flexible and uncomplicated planning of future workstations.

About the author: David Vilcek is the manager of workholding and assembly at Carr Lane Roemheld Manufacturing and can be reached at 636.779.5307 or dvilcek@clrh.com

Centerless grinding forms a part

Features - COVER STORY

When people think about centerless grinding, they often think of a finishing operation or a thru-feed operation to reduce the diameter of a part. However, Glebar Co. President John Bannayan says he’s more than ready to offer a different look at the process.

“In general, some people just don’t understand where grinding fits in for medical devices, and that’s what Glebar is able to come in and explain,” Bannayan says. “While the common thought is part finishing, our experience with materials – from super magnets and fiberglass to shape-memory alloys – allows centerless grinding of finished products with very precise diameters. Because form grinding has the same technique that makes a check valve, this can be used to grind a carbon-fiber ball or anything similar. So from form and plunge grinding, users can go from a cylinder to a finished part in one shot.”

Grinding solutions have offered users improvements in throughput by up to 30x while enhancing the quality of products and efficiency of operations.

Machine and vision

Centerless grinding, used for medical manufacturing, produces precision parts such as guidewires for stenting procedures and shavers used in arthroscopic surgery. The CAM.2 and the GT-610-CNC grinders find strong use within medical manufacturing, with the CAM.2 being the most widely used system for guidewire production.

“The CAM.2 is designed to address the growing cost of healthcare, particularly regarding minimally invasive procedures. Able to produce complex shapes in cylindrical components, it is a micro-machining center that can profile grind a 0.0090" diameter wire down to 0.0015" in diameter, maintaining length tolerances better than 0.0020" and diameter tolerances better than 0.0002" across an unlimited length of product,” Bannayan explains. “Since this machine is fully automatic, an operator can manage a five-machine cell, making this machine the industry standard for guidewire production.”

A newer powerhouse in the medical market, the GT-610-CNC, offers repeatability with the built-in CNC dresser, automating the process and helping minimize down time between dressing cycles. Built-in software wizards, configured for a part family, further reduce setup times and programming times. Surgical tools 0.1320" in diameter can be profile ground to better than 0.0001" in 9 seconds, producing mirror 3Ra to 5Ra surface finishes.

Bannayan says Glebar engineers took the same techniques used for grinding titanium fasteners for large aerospace producers – who are grinding six fasteners at a time versus one – and applied those to develop additional capabilities for the GT-610-CNC, which is not only used to manufacture fasteners but is also finding strong use in the production of shavers used in arthroscopic surgeries. These surgical tools consist of an inner and outer tube. The inner tube has a radial shape on its tip. A window in the outer tube exposes sharp teeth on the inside tube, which rotates at high speeds. While the teeth are typically produced on a different machine, tube form production occurs on the GT-610-CNC.

Arthroscopic shaver – grinding two mating metal components

Two tubes are assembled with as minimum a gap between the two parts as possible – as small as 0.0005" – so that the inner tube moves freely inside the outer tube without allowing debris to catch between the surfaces. Using the Glebar GT-610-CNC to in-feed grind the shape of the inner tube, engineers were able to maintain a ±0.0002" tolerance on the elliptical tip dimensions.

At the same time, they ground three diameter features to within 0.0002" per diameter, maintaining a TIR of 0.0001" and producing a smooth 9 Ra surface finish on 304V stainless steel with a ±0.001" wall thickness. Next, users removed 0.012" in stock for the majority of the part and 0.004" off the tip geometry. The entire fully automated process was done in less than 20 seconds, adjusting for part length variation, heat expansion, and a near zero tip geometry requirements. The process reduced previous scrap rates due to tip geometry imperfections, as well as eliminated an extra step in the manufacturing method which left unacceptable tool marks on the surface.

For the outer sleeve, a GT-610 thru-feed grinder is used to grind the OD of the blank tubes, maintaining a surface finish between 3RMS to 6RMS and maintaining a comfortable 2Cpk to 3Cpk on the outside diameter of the part. Material removal of 0.005" with a tolerance requirement of ±0.0005" was met easily in a fully automated turnkey process.

“The biggest challenge faced is getting those inner and outer tubes to have zero clearance between the surfaces. So we are grinding them, but not how one would normally think,” Bannayan says. “Normally an engineer would think of an in-feed grinding process, but we’ve taken it one step further. Because of the different lengths of the tubes, it makes it difficult to get essentially a zero tolerance on the curve and to get that shape.”

Glebar engineers’ approach is to have the machine load the part, measure the length of the tube, and then move the whole work rest laterally (a patent-pending process) against the face of the wheel to produce the desired shape. With this design, machinists are using parts of the grinding wheel that previously weren’t accessible.

Typically, processes to produce arthroscopic shavers would require a plunge grind and a turning operation. However, with the Glebar GT-610-CNC, users are able to combine the two operations.

Enhancing this process is the machine’s inclusion of a profile inspection system, Glebar’s P4K, originally designed for guidewire production. It’s a laser gage with a linear motor on it, or as Bannayan calls it, a CAT scan of any kind of cylindrical-shaped part.

Users are able to scan the tube, or multiple tubes, and feed that data back to the machine, with the machine automatically changing not only the diameter position but also the dress profile. Therefore, when there are very complex cylindrical shapes machinists need to dress, they can feed that information back from a gaging system and automatically modify the dress on the grinding wheel.

More time-consuming traditional methods would be for the operator to run a part, take it to an optical comparator or another vision system, apply an overlay, take it back to the machine, make machine adjustments, and then run another part, repeating the above steps again, as needed.

“The vision system we have on the machines is a mature product, designed for a range of applications that takes a diameter measurement every 30 millionth of an inch,” Bannayan explains. “The machine operator is able to define the points of measurement with diameter, length, surface finish, and more. When producing the arthroscopic shavers, machinists look at diameters and points on a software-generated overlay of the system, and those points are fed back to the machine. The machine can reshape or resharpen the grinding wheel to get back to a production run faster.”

Medical market glance

“We have always been in a range of markets with our grinding machines. With guidewire manufacturing, doctors were performing too many stenting procedures without a confirmed need. So, the idea came about to mill a slat on a 0.002" diameter guidewire at the tip so a chip could be bonded to it. That chip would measure pressure and temperature at the point of blockage, feeding back that information to the doctor, offering numbers to prove if there is a blockage that needed to be addressed. However, to produce that slat we needed to grind a very small flat with a very high tolerance of ±0.0001" so the chip could be assembled on the guidewire tip. It’s the requirements as miniscule and precise as these that keep our engineers continuing to advance the technology available on our grinding machines. This is also what pushes us to develop machines that are very intuitive so they can be run by the range of skilled workers entering the market while holding micron tolerances and high-quality.” ~ John Bannayan

Skill sets and technology

Manufacturing is facing a shortage of skilled workers, and finding skilled grinders is even more of a challenge. Addressing these obstacles is what has led Glebar engineers into advancing the machine technology while simplifying from a process standpoint.

“I think the education system is failing us in the manufacturing sector,” Bannayan says. “There are not enough people going into this trade in general, and it’s becoming harder to get young people involved in this sector. In our company, we have employees that came to us knowing zero and we have trained them from the ground up.

Bannayan says machine technology can ease the struggles. Machinists are able to operate four or five machines with ease. The technology enables the operator to load bundles of flexible wire, and then allows the system to singulate the product, strip it out of the bundle, and feed it into a machine. With this more automated process, the need for higher skill sets is reduced.

Glebar officials work with two local technical schools and some of their biggest successes have been veterans returning from service.

“We have hired some veterans who have taken a few CNC machining classes locally, and then we train them on our systems. Our success has been great, with some of them travelling around the country installing and servicing our machines as well as training machinists on our machines,” Bannayan says. “These technicians are able to do a complete rip-down and set-up of our very complex machines. I know if the U.S. government trusts them with nuclear subs, we can certainly trust we have a qualified person working on our machines.”

Glebar grinding machines have been running on computers and touchscreens since the late 1980s, and have subnets and IP addresses. This has kept the machines current with the move toward connected plants as well as the ability to troubleshoot from any location. Similar to how the installed inspection system goes through a company network and back to the machine, the system is configurable for each customer’s use, with Glebar technicians able to get device feedback on machine issues and failures.

Additional work the staff at Glebar finds satisfying is getting involved in projects from the start. This gives them the ability to look at the pre- and post-process grinding operation to see how they can take cost or production time out of the equation. Customizing the machines to add attachments or functions so a part can remain on the grinder for all stages is one way to achieve savings for customers, as well as increasing production time and quality.

Formally known as DAMCO Inc., Plastic Molding Manufacturing started in 1968 as a plastic injection molder and single-source manufacturer for thermoplastic injection-molded components. During the past five years, the company has acquired four additional plastic companies to expand manufacturing across the United States, with multiple molding presses, automated machines, product development, and analysis capabilities.

The company’s 5,000ft2 cleanroom located in its Massachusetts facility specializes in medical and healthcare products with strict production requirements.

Two-shot molding

Plastic Molding Manufacturing’s cleanroom is equipped with standard horizontal clamp presses and a vertical rotary shuttle table for insert over-molding. The cleanroom is regulated by clean air flow patterns, continuous positive air pressure, and controlled temperature and humidity, which prevents the concentration of airborne particles and contaminates.

The company’s Connecticut facility has four two-shot machines currently in operation. Two-shot presses include family mold and two-part number capabilities to save on cost and production.

In all, the company has 82 injection molding machines, including five two-shot machines.

Allrounder applications

Multi-way valves for intravenous drip therapy are manufactured with Allrounder injection molding machines in large Class 8 cleanrooms. The valve systems are also assembled and put in their primary packaging. To ensure correct operation, stringent tolerances must be maintained during injection molding.

Dental drills made from PEEK only remove carious material, unlike their metal counterparts that can cut tooth enamel. The tiny drills are produced in a single step by Plastic Molding Manufacturing and similar companies for dental practices as cost-effective, ready-to-use, disposable items. An electric injection molding machine from Arburg’s Alldrive series ensures precision.

In docked cleanroom cells, a 6-axis robotic system places the dental drills in blister packs. These are individually perforated, printed, and removed from the cell in units of 10 by a conveyor belt. No refinishing or sterilization is required prior to use.

An Allrounder 370 injection molding machine produces two tiny drills in a cycle time of around 30 seconds. Because tolerances measured in the hundredth of a millimeter range have to be met, all the axes important for part quality, such as injection, dosage, and mold movements are driven electrically.

Two drills are automatically packaged simultaneously with the injection molding cycle. A flexible 6-axis robotic system moves to a number of positions within the room for this purpose. It removes the molded parts from the mold, sets them onto a cooling station, and then inserts them the right way around in the blister packaging.

The robotic system and packaging system are docked to the machine with a sealed guarding. Together with the clean air modules that cover the entire working area, a completely encapsulated cleanroom cell is created that meets the requirements of Cleanroom Class 7.

Hormone rings made from liquid silicone rubber (LSR) and used by women for HIV prevention can also be manufactured by Arburg’s Allrounder machines. The most stringent hygiene and product quality requirements must be met during production. The special advantage: before injection molding, an agent is mixed into the liquid silicone that provides protection against HIV.

A production cell built around an Allrounder 520A, produces LSR vaginal rings in large unit volumes. As the main contractor, Arburg bears the complete responsibility. The cleanroom application was developed in cooperation with Arburg partners Rico and 2KM.

Man over machine

Plastic Molding Manufacturing’s CEO, George Danis says reshoring has been key in the company’s growth.

“With our goals in reshoring manufacturing we have made appropriate adjustments in our capabilities and services to make sure we can provide stronger local services to exceed our customers’ expectations,” he says. “We plan to continue adding state-of-the-art machines and to improve our services to help bring manufacturing back to the United States, creating jobs to help improve the economy.”

Danis says the company implements continuous training and maturing to ensure its employees and equipment are providing customers with superior service. The company’s equipment choices coincide with each facility’s needs, updates, and manufacturing advancements.

Smart insulin patch could replace injections for diabetes

Departments - 1 Last Look

Painful insulin injections could become a thing of the past thanks to researchers at the University of North Carolina (UNC) and North Carolina State University (NC State). The solution is a smart insulin patch that can detect increases in blood sugar levels and secrete doses of insulin into the bloodstream whenever needed.

The patch – a thin square no bigger than a penny – is covered with more than 100 tiny needles, each about the size of an eyelash. The microneedles are packed with microscopic storage units for insulin and glucose-sensing enzymes that rapidly release their cargo when blood sugar levels get too high.

The study found that the painless patch could lower blood glucose in a mouse model of Type 1 diabetes for up to nine hours. More pre-clinical tests and subsequent clinical trials in humans will be required before the patch can be administered to patients, but the approach shows great promise.

“We have designed a patch for diabetes that works fast, is easy to use, and is made from nontoxic, biocompatible materials,” says co-senior author Zhen Gu, Ph.D., a professor in the Joint UNC/NC State Department of Biomedical Engineering.

Researchers have tried to remove the potential for human error in insulin therapy by creating closed-loop systems that directly connect devices that track blood sugar and administer insulin. However, these approaches involve mechanical sensors and pumps with needle-tipped catheters that have to be stuck under the skin and replaced every few days.

Gu and his colleagues chose to emulate the body’s natural insulin generators, beta cells. These cells make and store insulin in tiny sacs called vesicles. They also behave like alarm call centers, sensing increases in blood sugar levels and signaling the release of insulin into the bloodstream.

“We constructed artificial vesicles to perform these same functions by using two materials that could easily be found in nature,” says Jiching Yu, a Ph.D. student in Gu’s lab. The first material was hyaluronic acid, a natural substance that is an ingredient of many cosmetics; and second was 2-nitroimidazole, an organic compound commonly used in diagnostics. The researchers connected the two to create a new molecule with one end that was water-loving, hydrophilic, and one that was water-fearing, hydrophobic. A mixture of these molecules self-assemble into a vesicle, with hydrophobic ends pointing inward and hydrophilic ends pointing outward.

The result was millions of bubble-like structures, each 100x smaller than the width of a human hair. Into each of these vesicles, researchers inserted a core of solid insulin and enzymes designed to sense glucose.

In lab experiments, when blood sugar levels increased, the excess glucose crowded into the artificial vesicles. The enzymes then converted the glucose into gluconic acid, consuming oxygen all the while. The resulting lack of oxygen or hypoxia made the hydrophobic NI molecules turn hydrophilic, causing the vesicles to rapidly fall apart and send insulin into the bloodstream.

Rather than rely on the large needles or catheters, researchers incorporated the balls of sugar-sensing, insulin-releasing material into an array of tiny needles.

Gu created these microneedles using the hyaluronic acid used in nanoparticles, only in a more rigid form so the needles were stiff enough to pierce the skin. When this patch was placed on the skin, the microneedles penetrated the surface, tapping into the blood flowing through the capillaries just below.

Researchers gave one set of mice a standard injection of insulin and measured the blood glucose levels, which dropped down to normal, but then quickly climbed back into the hyperglycemic range. When the researchers treated another set of mice with the patch, they saw blood glucose levels brought under control within 30 minutes, which stayed that way for several hours.

Researchers found that they could tune the patch to alter blood glucose levels only within a certain range by varying the dose of enzyme contained within each of the microneedles.

“The hard part of diabetes care is not the insulin shots, or the blood sugar checks, or the diet, but the fact that you have to do them all several times a day, every day for the rest of your life,” says John Buse, the director of the North Carolina Translational and Clinical Sciences Institute and past president of the American Diabetes Association. “If we can get these patches to work in people, it will be a game changer.”

The researchers’ eventual goal, Gu says, is to develop a smart insulin patch that patients would only have to change every few days.